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d-cycloserine enhancement of exposure therapy for social anxiety disorder depends on the success of exposure sessions
Open accessAbstract
Objective The evidence for the efficacy of D-cycloserine (DCS) for augmenting cognitive behavioral therapy (CBT) for anxiety disorders has been mixed. Guided by preclinical research and initial findings from a small-scale study involving humans, we tested the hypothesis that DCS enhancement of exposure therapy would be specific to successful exposure sessions. Method Medication-free adults with generalized social anxiety disorder (N = 145) received 50 mg of DCS or placebo 1 h before each of 5 exposure sessions that were part of a standardized 12-session group CBT protocol. Participants provided fear ratings at the beginning and just before the end of exposure exercises. Independent raters, blind to group assignment, administered the clinical global impression improvement and severity scales at each session and at posttreatment. Results Mixed-effects analyses revealed that, among patients who reported low fear at the end of an exposure session, those who had received DCS evidenced significantly greater clinical improvement at the next session, relative to those who had received placebo. In contrast, when exposure end fear was high, patients receiving DCS exhibited less clinical improvement at the following session than patients receiving placebo. Similarly, patients who had received DCS evidenced lower clinical severity at posttreatment, relative to patients who had received placebo, only when their average end fear for medication-augmented sessions had been in the low to moderate range. Finally, these moderating effects of exposure success as indexed by end fear were not better accounted for by within-session extinction. Conclusions The efficacy of DCS for augmenting exposure-based CBT depends on the success of exposure sessions. These findings may help guide the development of an algorithm for the effective use of DCS for augmenting exposure-based CBT. Trial registry http://www.ClinicalTrials.gov, ID# NCT00633984, http://www.clinicaltrials.gov/ct2/show/NCT00633984.
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“administration of the NMDAR partial agonist D-cycloserine (DCS) enhances the acquisition of the extinction memory”
From Retrieval-Dependent Mechanisms Affecting Emotional Memory Persistence: Reconsolidation, Extinction, and the Space in Between (2020) · cites this paper as Smits et al., 2013
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“Another consideration is that recent studies in anxiety states suggest that the quality of exposure therapy session is crucial in the success of DCS as evidenced by improvement with successful exposure therapy plus DCS and detriment with unsuccessful exposure therapy plus DCS.(23,24)”
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“However, the efficacy of DCS has been variable across studies, with several evidencing strong augmentative effects and several showing either relatively weak or no effects [128].”
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“To test whether DCS might only augment sessions during which anxiety reduction has appeared, 2 RCTs have been reanalyzed by Smits et al.(40,41) In the first placebo-controlled study, 29 patients with height phobia received DCS or placebo directly after two 30-minute virtual reality exposure sessions.”
Zaizar, E. D., Gonzalez-Lima, F., & Telch, M. J. (2018) · Contemporary Clinical Trials · doi:10.1016/j.cct.2018.07.012 · Cited by 19
Marchetta, E., Mancini, G. F., Morena, M., & Campolongo, P. (2022) · Current Neuropharmacology · doi:10.2174/1570159x21666221207162750 · Cited by 17
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Hormonal, reproductive, and behavioural predictors of fear extinction recall in female rats
Tang, S., & Graham, B. M. (2020) · Hormones and Behavior · doi:10.1016/j.yhbeh.2020.104693 · Cited by 15
Sudden gains in internet-based cognitive behavior therapy for obsessive-compulsive disorder
Hamdeh, A. A., Bjureberg, J., Lenhard, F., Hedman‐Lagerlöf, E., Flygare, O., Lundström, L., Ljótsson, B., Mataix‐Cols, D., Rück, C., & Andersson, E. (2018) · Journal of Obsessive-Compulsive and Related Disorders · doi:10.1016/j.jocrd.2018.12.005 · Cited by 15
Does fear reduction predict treatment response to exposure for social anxiety disorder?
McGlade, A. L., Treanor, M., Kim, R., & Craske, M. G. (2022) · Journal of Behavior Therapy and Experimental Psychiatry · doi:10.1016/j.jbtep.2022.101833 · Cited by 14
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Advances in Psychopharmacology for Anxiety Disorders
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d-Cycloserine and estradiol enhance fear extinction in nulliparous but not primiparous female rats
Tang, S., & Graham, B. M. (2019) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2019.107088 · Cited by 16
Otto, M. W., Pachas, G. N., Cather, C., Hoeppner, S. S., Moshier, S. J., Hearon, B. A., Ward, H. B., Laffer, A., Smits, J. A. J., & Evins, A. E. (2018) · Cognitive Behaviour Therapy · doi:10.1080/16506073.2018.1476908 · Cited by 11
Self-citationLeyfer, O. T., Carpenter, A. L., & Pincus, D. B. (2018) · Child Psychiatry & Human Development · doi:10.1007/s10578-018-0837-1 · Cited by 11
“[49] for individuals with social anxiety disorder.”
Looking Beyond Fear and Extinction Learning: Considering Novel Treatment Targets for Anxiety
Britton, J. C., Evans, T. C., & Hernandez, M. V. (2014) · Current Behavioral Neuroscience Reports · doi:10.1007/s40473-014-0015-0 · Cited by 11
Effects of d -cycloserine on individual differences in relapse of fear
King, G., Graham, B. M., & Richardson, R. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.02.005 · Cited by 9
“Similar findings have since been reported in clinical trials where the success of the exposure session determined whether DCS resulted in greater clinical improvement or not (Smits et al., 2013b; Tart et al., 2013).”
d-Cycloserine-Augmented Behavior Therapy for Body Dysmorphic Disorder: A Preliminary Efficacy Trial
Weingarden, H. M., Mothi, S. S., Ladis, I., Hoeppner, S. S., Reese, H. E., Timpano, K. R., Siev, J., Rasmussen, J. L., Ragan, J. D., Dougherty, D. D., et al. (2019) · Cognitive Therapy and Research · doi:10.1007/s10608-019-10015-0 · Cited by 7
Cognitive-Behavioral Therapy Enhancement Strategies
Tolin, D. F., Lord, K. A., & Knowles, K. A. (2024) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2024.02.005 · Cited by 7
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A precision medicine approach to pharmacological adjuncts to extinction: A call to broaden research
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Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq
Malan‐Müller, S., Fairbairn, L., Daniels, W. M. U., Dashti, M. J. S., Oakeley, E. J., Altorfer, M., Kidd, M., Seedat, S., Gamieldien, J., & Hemmings, S. M. J. (2015) · Metabolic Brain Disease · doi:10.1007/s11011-015-9727-4 · Cited by 5
“2010), PTSD (Smits et al. 2013; de Kleine et al. 2012) and panic disorder (Otto et al.”
BackgroundInfluentialMalan‐Müller, S., Fairbairn, L., Hart, S. A., Daniels, W. M. U., Dashti, M. J. S., Kidd, M., Seedat, S., Gamieldien, J., & Hemmings, S. M. J. (2017) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000176 · Cited by 6
“DCS treatment has also been used to augment exposure therapy (Smits et al., 2013), especially in patients with more severe post-traumatic stress disorder (PTSD) (de Kleine et al., 2012), and a decrease in the rate of relapse was observed following DCS augmentation of exposure-based cognitive…”
MethodThe Nature and Treatment of Social Anxiety
Carpenter, J. K., Curtiss, J. E., & Hofmann, S. G. (2017) · Wiley eBooks · doi:10.1002/9781118877142.ch5 · Cited by 6
Self-citationPost-extinction L-DOPA administration to reduce the return of fear in humansPreprint
Gerlicher, A. M. V., Ilhan-Bayrakcı, M., Tüscher, O., & Kalisch, R. (2022) · PsyArXiv (OSF Preprints) · doi:10.31234/osf.io/rhnsa · Cited by 4
Pharmacological enhancement of fear extinction
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Mechanisms of Action in the Treatment of Social Anxiety Disorder
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Self-citationCombination Psychological and Pharmacological Treatments for Panic Disorder
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Self-citationExercise and Fear and Safety Learning
Azar, A., Hubert, T., Adams, T. G., Cisler, J. M., & Crombie, K. M. (2024) · Current topics in behavioral neurosciences · doi:10.1007/7854_2024_494 · Cited by 6
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“For example, in a study on patients with generalized social anxiety disorder, clinical improvement from one exposure therapy session to the next was enhanced if subjects reported low fear at the end of the session but not if they reported high fear (Smits et al., 2013).”
BackgroundLubin, R. E., Fitzgerald, H. E., Rosenfield, D., Carpenter, J. K., Papini, S., Dutcher, C. D., Dowd, S. M., Hofmann, S. G., Pollack, M. H., Smits, J. A. J., et al. (2023) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2023.06.008 · Cited by 4
Self-citationSmits, J. A. J., Kauffman, B. Y., Lee-Furman, E., Zvolensky, M. J., Otto, M. W., Piper, M. E., Powers, M. B., & Rosenfield, D. (2016) · Contemporary Clinical Trials · doi:10.1016/j.cct.2016.03.011 · Cited by 4
Self-citationEmpirical status of mechanisms of change.
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Self-citationA Comparison between Psychosocial and Pharmacological Treatments
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Self-citation
Metadata
- Authors
- Smits, J. A. J., Rosenfield, D., Otto, M. W., Marques, L., Davis, M. L., Meuret, A. E., Simon, N. M., Pollack, M. H., & Hofmann, S. G.
- Affiliations
- Southern Methodist University (US)
- Boston University (US)
- Massachusetts General Hospital (US)
- Rush University Medical Center (US)
- Corresponding author
- Hofmann, Stefan G.
- ORCID
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 47
- Issue
- 10
- Pages
- 1455-1461
- ISSN
- 0022-3956 (ISSN-L)
- PMC
- PMC3747985
- OpenAlex
- W2157504515
- Cited by
- 114
- References
- 41
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 7 · 2022: 6 · 2021: 3 · 2020: 4 · 2019: 9 · 2018: 17 · 2017: 15 · 2016: 9 · 2015: 19 · 2014: 14 · 2013: 3
- FWCI
- 20.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Psychiatric Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH075889, K23MH096029, R01MH078308)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
- Keywords
- D-cycloserine, social anxiety disorder, exposure therapy, cognitive behavioral therapy, drug augmentation, treatment response, treatment algorithm
- MeSH terms
- Adult, Antidepressive Agents, Anxiety Disorders, Cycloserine, Double-Blind Method, Fear, Female, Humans, Implosive Therapy, Male, Severity of Illness Index, Models, Statistical, Young Adult
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